期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 496, 期 4, 页码 1040-1046出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2018.01.093
关键词
Glioblastoma; Temozolomide resistance; MSH6; DNA mismatch repair; O-6-methylguanine-DNA methyltransferase
资金
- Natural Science Foundation of China [91229112, 30772238, 81472367, 81402054, 81401286]
- Scientific and Technological Project of Heilongjiang Province of China [GC12C303-1]
The impact of DNA mismatch repair (MMR) on resistance to temozolomide (TMZ) therapy in patients with glioblastoma (GBM) is recently reported but the mechanisms are not understood. We aim to analyze the correlation between MMR function and the acquired TMZ resistance in GBM using both relevant clinical samples and TMZ resistant cells. First we found increased expression of MSH6, one of key components of MMR, in recurrent GBM patients' samples who underwent TMZ chemotherapy, comparing with those matched samples collected at the time of diagnosis. Using the cellular models of acquired resistance to TMZ, we further confirmed the up-regulation of MSH6 in TMZ resistant cells. Moreover, a TCGA dataset contains a large cohort of GBM clinical samples with or without TMZ treatment reinforced the increased expression of MSH6 and other MMR genes after long-term TMZ chemotherapy, which may resulted in MMR dysfunction and acquired TMZ resistance. Our results suggest that increased expression of MSH6, or other MMR, may be a new mechanism contributing to the acquired resistance during TMZ therapy; and may serve as an indicator to the resistance in GBM. (C) 2018 Elsevier Inc. All rights reserved.
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